by Siim Land
It’s thought that leptin resistance is one of the main drivers of obesity[520]. That’s the reason people get obese in the first place and that’s why most diets fail. Leptin resistance results partly from hyperleptinemia by downregulating the cellular response to leptin[521]. Basically, too much leptin all the time makes the brain desensitized to the signals that say you’re satiated and nourished, thus promoting hunger, cravings, and obesity. It’s like the boy who cried wolf...
Leptin resistance walks hand in hand with insulin resistance both of which make you require to produce more leptin and insulin to signal the brain that there’s adequate energy.
Figure 72 Hyperglycemia causes insulin resistance,
which promotes leptin-resistance and obesity
If you look at the physiology and understand the principles of nutrient partitioning you’ll realize why the majority of people are obese. They’re simply eating too many carbohydrates too often which keeps them in a state of hyperinsulinemia. Add the constantly stressed out lifestyle laden with cortisol and cheap food into the mix and you’ll end up with this obesogenic hormonal concoction that’s about to explode any moment.
This is called the Carbohydrate-Insulin Hypothesis (CIH), which is based on the idea that insulin makes you fat. However, if you dig a bit deeper you’ll see that there’s clearly something missing. For instance, the Japanese have very low levels of obesity and heart disease despite eating a diet high in rice and carbs. Other countries with higher carbohydrate intake don’t suffer the same way either. Until they come into contact with refined carbs and sugars of the Western food industry that is...
Only after the introduction of processed foods from the West do traditional diets become fattening. This you can see happening in China and India who traditionally eat more carbohydrates but now get access to different indulgences and more added sugars. These countries cover nearly 1/3 of the world’s population and there’s another epidemic bound to happen. People in Japan have so far remained to be less affected by this global trend thanks to sticking to a more home-made cuisine and avoiding over-eating.
The Innuit have also been devoid of diabetes and obesity throughout their dietary history. Despite getting over 90% of their calories from red meat, seal fat, whale blubber, and fish, they didn’t die to heart disease or suffocate to the high amounts of saturated fat they were consuming. Unfortunately, after coming into contact with the white flour and sugar of modern people did they get more of those diseases. It’s not the meat, it’s what you eat the meat with...
These anthropological examples show that the Carbohydrate-Insulin Hypothesis has some truth to it but it’s not the entire picture. It’s important to understand the bigger milieu in which obesity and disease develop.
Now that this is covered, let’s address the deeper cause of the issue, which has been the problem all along – insulin resistance. Shall we begin?
Insulin Resistance
Your body wants to maintain a stable blood sugar level all the time – to be in homeostasis and complete balance. Whenever there’s an elevation in blood sugar the pancreas secretes the hormone insulin to store that glucose and stabilize blood sugar again. The cells sense insulin through insulin receptors that will signal the PI3K/Akt/mTOR signaling pathway[522].
Insulin Resistance is a condition where the cells don't respond normally to the elevation of insulin and are resistant to picking up glucose, thus causing high blood sugar. The beta cells in the pancreas continue to produce more insulin but to no avail. This keeps both blood sugar and insulin levels elevated for a longer time.
Hyperinsulinemia is a condition where there’s excess circulating insulin in relation to the amount of blood glucose. It’s associated with hypertension, diabetes, obesity, and metabolic syndrome[523]. This is one of the underlying issues that’s driving cardiovascular disease and other health disorders.
Symptoms of insulin resistance or glucose intolerance include uncontrollable hunger, increased thirst, high blood sugar, high blood pressure, brain fog, lethargy, lightheadedness, easy weight gain around the stomach, stubborn belly fat, elevated triglyceride and cholesterol levels.
In most cases, hyperinsulinemia is both a result and the driver of insulin resistance[524]. The two basically describe the same thing.
A study in Diabetologia took 12 non-obese men who got injected with higher and higher doses of insulin over the course of 40 hours[525]. At the end of the experiment, they showed a 15% decreased glucose tolerance, which is another way of saying they became 15% more insulin resistant. Another study took 15 healthy non-diabetic men who were given normal doses of insulin over 96 hours. By the end of it, their insulin sensitivity had dropped by 20-40%[526]. Essentially, frequently high insulin makes the body eventually insulin resistant. High and frequency are relative terms and context-dependent but in most cases, you don’t want to keep your insulin elevated at all.
Although chronic insulin resistance is quite harmful, it also has a beneficial adaptive mechanism. Under harsh metabolic conditions, insulin resistance helps to give the brain glucose that would otherwise be taken up by muscles[527]. It’s also thought to be a normal physiological response to sustained caloric surplus and overeating, in general, to protect the body against the accumulation of lipids[528]. Animals who eat a lot more calories than needed develop rapid insulin resistance and get obese very fast[529], especially if you feed them a lot of grains and carbs.
However, from the perspective of longevity, it’s not a good idea to have continuously elevated levels of blood sugar or insulin. First of all, it promotes fat gain and raises triglycerides, but secondly, it also keeps the body in a continuous state of dysfunctional mTOR signaling. You want to be more insulin sensitive so you’d clear your bloodstream from any excess glucose as fast as possible and get back into ketosis.
Guess what causes hyperinsulinemia and insulin resistance? You can predict that processed carbs and too much sugar play a major role but trans fats are another thing to be blamed for[530]. Fast food that combines a lot of salt, sugar, and fat with sweetened drinks is a perfect recipe for insulin resistance and over-eating because of their high caloric content and palatability[531].
Elevated levels of fatty acids and triglycerides have been found to be associated with insulin resistance as well[532]. However, the prolonged elevation of insulin and triglycerides is most commonly caused by the combination of carbs and fats that keep the blood sugar jacked up for longer. People who eat more fat tend to also eat a lot of carbs. Someone eating fat on a low carb diet will not spike insulin as much.
In Figure 73 you can see that the combination of carbohydrates with fats raises insulin significantly more than carbs alone. Also, note that protein and fats barely cause any difference in blood sugar or insulin. That comes to show why processed foods are so damaging on the metabolic level as well.
You don’t want to ever combine high-carb foods with high amounts of fatty acids because it’ll not only increase insulin much higher but also promotes more inflammation, oxidative stress, and metabolic disorders. Ironically, that’s exactly the combo you can get from a Happy Meal, Starbucks, McDonald's, or any other fast food joint. Unfortunately, you can still make the same error with healthy foods like frying potatoes in oils, making toast with eggs and bacon, or eating chocolate cake.
Figure 73 Basically, combining carbs with fat will also raise insulin much higher than alone.
That's why it's even more dangerous to be combining high fat foods with carbs.
Fructose, which is the sugar molecule of fruit, gets stored in the liver and can stimulate insulin production through a similar mechanism. Excess fructose can be very easily converted into triglycerides that will be rapidly stored as fat. A consistently high intake of carbohydrates and particularly fructose-sweetened beverages contribute to insulin resistance, which has been linked with obesity and weight gain[533]. Natural fruit is slightly less harmful because it contains a bit of fiber and other co-enzymes but it’s still very high in
fructose sugar that will drive up triglyceride production. For optimal longevity, you wouldn’t want to be consuming a lot of fruit every day.
Another contributing factor to insulin resistance is obesity or even just mild adiposity. Visceral fat, which is the type of fat you carry around your belly and organs will continuously release inflammatory cytokines and fatty acids into your system. Abdominal visceral fat is strongly correlated with insulin resistance and type 2 diabetes[534]. That’s why consuming excess fructose or carbohydrates drives this entire process – too many triglycerides being stored as visceral fat.
Low carb diets, avoiding processed sugar, and prolonged fasting have been found to be very effective in healing the pancreas and reversing insulin resistance.
Carbohydrate restriction helps with everything that causes metabolic syndrome, such as high blood sugar, weight gain, elevated insulin, and hypertension[535].
Diabetics who ate a normal diet were put on a ketogenic one for 2 weeks and they lowered their triglycerides by 35%, dropped total cholesterol by 10%, ate 30% fewer calories, dropped 4 pounds and improved their insulin sensitivity by 75%[536]!
Compared to a low carb ketogenic diet, a low-fat diet for four weeks has been seen to raise fasting glucose and insulin[537], which is the very opposite to what you want.
Ketogenic diets have been shown to be very effective at losing body fat in dozens of studies[538].
Beta-Hydroxybutyrate (BHB) the main ketone body has been found to inhibit histone deacetylases (HDACs) which lowers blood glucose and decreases insulin resistance[539].
If we know that a lot of the modern metabolic diseases are caused by hyperinsulinemia, inflammation and insulin resistance, then it doesn’t make sense to purposefully keep our blood sugar and insulin elevated all the time. It also contradicts the information we have about how insulin affects longevity in other species. To live a longer and healthier life, you obviously want to avoid obesity.
However, going very low carb for too long may cause peripheral insulin resistance. Rats fed the ketogenic diet with 95% of calories coming from fat develop hepatic insulin resistance, despite increasing energy expenditure and preventing weight gain[540]. This happens because of the same adaptive response that tries to preserve energy for the brain. In this context, it’s not dangerous and not that relevant because the diet itself doesn’t require a lot of insulin to clear the bloodstream from glucose. If you’re not eating that many carbs, then you don’t need extra insulin either. Decreased insulin signaling itself is still a good thing for increased longevity and the insulin resistance induced by carbohydrate restriction is an adaptive mechanism.
After keto-adaptation the body will use primarily ketones and lactate thus decreasing glucose demands but a small amount of glucose is still needed for certain vital organs. If you’re already insulin sensitive and lean, then this kind of mild insulin resistance is needed in the context of a ketogenic diet. Without this and gluconeogenesis, your brain wouldn’t be able to get the glucose it needs. If you were to be on a ketogenic diet for some time and then took an oral glucose test at the doctor you may potentially score as insulin resistant just because your body wouldn’t know how to respond that quickly. You’d have to take a second test after your body has managed to get used to insulin again. To prevent any long-term negative consequences to that, it’s still a good idea to occasionally dip in and out of ketosis so your body would maintain its glucose tolerance and become more insulin sensitive again. That’s why metabolic flexibility is characterized by both improved insulin sensitivity and glucose tolerance.
Here are more ways of protecting yourself against insulin resistance:
Exercise - Working out and physical activity is one of the biggest determining factors to how insulin sensitive you are[541]. The main cause is thought to be muscle contractions causing the glucose receptor GLUT4 to translocate to the membrane. GLUT4 can improve the uptake of glucose through a distinct mechanism that of insulin[542]. This will lower blood glucose and insulin, preventing hyperinsulinemia.
Get Enough Sleep - Sleep deprivation has been shown to trigger insulin resistance in healthy subjects. Even just a single night of not enough sleep makes you borderline pre-diabetic in the short term. After a bad night’s sleep, your glucose tolerance for the next day is going to be drastically lower.
Avoid Smoking - Smoking also induces insulin resistance and causes atherosclerosis[543]. It’s causing similar damage to the arteries as does excess glucose in the bloodstream. Eating low carb high fat while still smoking is as bad as eating junk food.
Lower Your Stress - Chronic stress and cortisol are known to raise blood sugar, blood pressure and insulin, which over the long term will definitely lead to insulin resistance[544]. Cortisol literally impairs the uptake of glucose by reducing the translocation of glucose transporters such as GLUT4[545]. It also keeps that stubborn visceral fat around your belly. Mindfulness-based stress-reducing activities like meditation and yoga have been shown to improve insulin resistance[546].
Get Enough Sunshine – Vitamin D deficiencies are associated with insulin resistance[547]. It’s an essential steroid hormone that influences every cell in your body, including insulin secretion. Vitamin D is also important for protecting against heart disease. The best way to synthesize vitamin D would be to get it straight from the sun but taking a D3 supplement can also be helpful.
Lower Inflammation - Funny enough, in rats, insulin resistance can be alleviated by fish oil supplementation[548]. This may be partly due to the anti-inflammatory properties of omega-3s that help to fight the inflammation caused by sugar.
At this point, we should move on with the secondary consequence of elevated blood sugar and insulin, which sets this entire party on fire, literally.
Inflammation and Advanced Glycation End Products
Chronically high levels of blood glucose have many detrimental effects on your health. We already know about insulin resistance and the increased risk of metabolic syndrome but hyperinsulinemia also directly damages the body.
Chronic inflammation is connected to most modern diseases, such as insulin resistance, metabolic syndrome, diabetes, and atherosclerosis[549]. In fact, all of those ailments could be umbrellaed under this condition. That’s why inflammatory oils, processed food, high fructose corn syrup (HFCS), and high amounts of sugar drive systemic inflammation throughout the entire system.
Advanced Glycation End-Products (AGEs) are these compounds that get formed when sugar molecules react with proteins or fats. AGEs are related to accelerated aging, diabetes, increased inflammation, and mitochondrial dysfunction. AGEs can also interfere with insulin signaling by decreasing insulin secretion, thus promoting insulin resistance[550].
Inflammation from food and AGE formation creates oxidative stress, which increases gut permeability as well. ’Leaky Gut,’ as it’s called, allows bacteria, undigested food particles, and unmetabolized toxins to enter the bloodstream and inflame different tissues of the body and lead to obesity[551].
Excess amount of processed carbs and sugars, especially HFCS are linked to inflammation. Even low to moderate sugar-sweetened beverage consumption impairs glucose and lipid metabolism, which promotes inflammation[552]. Better think twice before grabbing for that juice, energy drink, or even diet soda.
It’s important to differentiate processed carbs from natural carb foods because they create a different metabolic reaction. In fact, some of the sugars in vegetables and fruit have anti-inflammatory effects[553]. Probably due to their polyphenol and fiber content. However, in the context of insulin and longevity, you don’t want to be consuming excess sugar or carbs for nothing.
Even though you may not get diabetes from eating a few apples, the signaling pathways will still be the same with a difference being only in the degree. Additionally, you can gain most of the health benefits of these plant polyphenols from much better sources with fewer carbs, zero insulin, and greater improvement on longevity. If you have to justify eating grapes to get y
our polyphenols whereas you could get more of them from cruciferous vegetables then you’re making a bad trade.
Glycation end products have been shown to promote cancer in animals but not in humans[554][555]. Nevertheless, I think it’s still a wise idea to limit your exposure to them because they’ll accelerate aging.
When it comes to other foods, then cooking and processing food in general increases the amount of AGEs and other free radicals, such as heterocyclic amines (HAs), and polycyclic aromatic hydrocarbons (PAHs). HAs and PAHs get formed when you cook, grill, fry, or smoke food at high heat. That’s why it’s never a good idea to char your bacon super crisp or let the vegetables turn too crisp – it causes glycation that’s bad for your skin and long-term health.
The highest amount of glycation end products can be found in charred meat cooked over a barbeque[556]. Could it be another reason to limit meat consumption? You definitely don’t want to eat BBQ all the time. Fortunately, marinating beef for an hour before cooking reduced its AGE formation by more than half, and marinades can lower HAs in meat by up to 90%[557].
One study found that omnivores tend to have higher dietary AGE intake than vegetarians, but vegetarians actually end up with higher AGE concentrations in their plasma[558]. The authors figured that this was due to the increased fructose intake of vegetarian diets, which induces oxidative stress to the liver. Leafy vegetables also have a lot of PAHs, comparable to the levels in smoked meat even.
AGE formation can be inhibited by the amino acid carnosine, which is found in meat[559]. However, the amounts of carnosine are quite small from natural foods and if you’re really worried about it, then you should take a carnosine supplement instead. Either way, AGEs from natural meat aren’t that big of an issue, unless you overcook it all the time and expose your food to other free radicals.